Preparation process of 4, 6-dimethoxy-2-((phenoxy carbonyl) amino)-pyrimidine

Abstract

The invention relates to the technical field of pesticide intermediates, and discloses a preparation process of 4, 6-dimethoxy-2-((phenoxy carbonyl) amino)-pyrimidine, which comprises the following steps: S1, preparing 2-amino-4, 6-dimethoxypyrimidine, triphosgene, phenol, a solvent and a catalyst; s2, dissolving triphosgene in part of the solvent to prepare a solvent solution of the triphosgene; and S3, adding the 2-amino-4, 6-dimethoxypyrimidine and the residual solvent into a four-neck flask, stirring and dissolving, adding a catalyst, and dropwise adding a solvent solution of the triphosgene. Solid phosgene is used as a raw material instead of high-toxicity phenyl chloroformate or gaseous phosgene in the prior art, toluene and xylene which are low in price and easy to layer with water are matched as solvents, and cost-controllable triethylamine or pyridine is selected as a catalyst, so that the raw material cost and the safety risk are reduced, and the economic requirements of industrial production are met.

Description

Technical Field

[0001] This application relates to the field of pesticide intermediate technology, specifically a preparation process for 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. Background Technology

[0002] 4,6-Dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine is an important intermediate in the preparation of sulfonylurea herbicides such as pyrimisulfuron, bensulfuron-methyl, and pyrimisulfuron. Since its purity directly affects the purity and quality of downstream sulfonylurea herbicides, the preparation technology of high-purity 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine is one of the important technologies for producing qualified or high-purity sulfonylurea herbicides. Its molecular structure contains active groups such as a pyrimidine ring and a carbamate group, and it can also be used in the pharmaceutical field to synthesize drug molecules with specific biological activities.

[0003] Traditional methods typically use 2-amino-4,6-dimethoxypyrimidine and phenyl chloroformate as raw materials to prepare the target product. However, phenyl chloroformate has drawbacks such as high toxicity, poor stability, and volatility, leading to significant safety hazards during production, transportation, and storage, and also resulting in high preparation costs. Summary of the Invention

[0004] This application provides a preparation process for 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine, which solves the problems of significant safety hazards and high preparation costs associated with traditional processes during production, transportation, and storage.

[0005] To achieve the above objectives, this application provides the following technical solution: a preparation process for 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine, comprising the following steps: S1. Prepare 2-amino-4,6-dimethoxypyrimidine, solid phosgene, phenol, solvent and catalyst; S2. Dissolve solid phosgene in a portion of the solvent to prepare a solvent solution of solid phosgene; S3. Add 2-amino-4,6-dimethoxypyrimidine and the remaining solvent to a four-necked flask, stir to dissolve, add the catalyst, and then add the solvent solution of the solid phosgene dropwise. S4. After the addition is complete, the temperature is raised and the reaction is maintained at this temperature. Then phenol is added, the temperature is raised again, and the reaction is maintained at this temperature again to obtain the reaction solution. S5. The reaction solution is then cooled to room temperature, washed with water until neutral, and separated to obtain the organic phase. The organic phase is then dried and filtered. S6. The filtered organic phase is subjected to vacuum distillation to recover the solvent, and a crude product is obtained. The crude product is purified by recrystallization to obtain pure 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine.

[0006] By adopting the above technical solution, the addition of solvent and catalyst creates a suitable reaction environment for the reaction, and each raw material participates in the reaction according to the process settings, ensuring the smooth start of the reaction; Dissolve solid phosgene in a solvent to form a solution, which facilitates subsequent dropwise addition and ensures that the solid phosgene is evenly dispersed in the reaction system, avoiding reaction abnormalities caused by local aggregation; Mix 2-amino-4,6-dimethoxypyrimidine with the remaining solvent and stir to dissolve, ensuring that the reactants are fully dispersed. The addition of the catalyst can promote the reaction kinetics. The dropwise addition of solid phosgene solution allows the reaction to proceed step by step, avoiding side reactions caused by excessively fast reaction rates. After the addition is complete, the temperature is raised and maintained in stages to allow the 2-amino-4,6-dimethoxypyrimidine to react fully with solid phosgene to generate the key intermediate. Then, phenol is added to continue the reaction, so as to achieve the step-by-step orderly reaction and ensure the formation pathway of the target product. After the reaction solution is cooled, it is washed with water until neutral to remove soluble impurities in the reaction system. Liquid-liquid separation separates the organic phase from the aqueous phase. Drying removes residual water from the organic phase, and filtration further removes solid impurities, improving the purity of the materials to be processed later. Solvent recovery by vacuum distillation enables the reuse of solvent, and recrystallization purification of crude product can remove residual raw materials and by-products to obtain high-purity 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. Through the above steps, the generation of by-products during the reaction can be reduced, solvent recycling reduces resource consumption, and post-treatment operations such as washing and filtration reduce harmful components in waste, ultimately achieving a low pressure on the treatment of waste and an environmentally friendly effect.

[0007] Preferably, in step S1, the molar ratio of 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol is 1:(1.0-1.5):(1.0-1.2).

[0008] By adopting the above technical solution, the amino group in the molecular structure of 2-amino-4,6-dimethoxypyrimidine provides a reaction site for the formation of the target product. Solid phosgene can react with the amino group to generate an intermediate, and phenol can further react with the intermediate to form the carbamate structure in the target product. The three work together to ensure that 2-amino-4,6-dimethoxypyrimidine fully participates in the reaction, reduces the residue of unreacted raw materials, and avoids the increase of side reactions caused by the excess of a single component, thus ensuring that the reaction proceeds in an orderly manner according to the set path.

[0009] Preferably, in step S1, the solvent is one or more of toluene and xylene.

[0010] By adopting the above technical solution, toluene and xylene can dissolve 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol, providing a homogeneous reaction medium and ensuring full contact between the reactants. Both have obvious stratification characteristics with water, facilitating the separation of the organic and aqueous phases after the reaction and simplifying post-processing operations. They are easily recovered under vacuum distillation conditions and can be reused in the reaction. At the same time, they have low toxicity, which reduces the environmental impact during the reaction process compared to highly toxic solvents, lowers the content of toxic components in waste gas and waste liquid, and further reduces resource consumption through recycling.

[0011] Preferably, the catalyst is one or more of triethylamine and pyridine.

[0012] By adopting the above technical solution, triethylamine and pyridine are both well miscible with toluene or xylene in the reaction system, and can be uniformly dispersed in the reaction medium to contact the reactants, promoting the initiation of the reaction between 2-amino-4,6-dimethoxypyrimidine and solid phosgene, driving the formation of intermediates and subsequent reactions with phenol, and ensuring the smooth progress of the reaction. Triethylamine and pyridine are chemically stable and do not easily decompose under reaction conditions, thus not introducing additional impurities into the reaction system and ensuring product purity. The separation of triethylamine and pyridine from reaction products and solvents can be achieved through post-processing steps such as washing and distillation, without leaving residues in the final product. Furthermore, no large amount of harmful byproducts are generated during use. Combined with the recovery and reuse of toluene or xylene, the reaction conditions are mild, helping to improve product yield and content.

[0013] Preferably, the amount of catalyst used is 0.05-0.1 times the molar amount of 2-amino-4,6-dimethoxypyrimidine.

[0014] By adopting the above technical solution, the ratio of the amount of catalyst to the molar amount of 2-amino-4,6-dimethoxypyrimidine ensures that the catalyst can fully exert its catalytic effect, and promotes the reaction of 2-amino-4,6-dimethoxypyrimidine with solid phosgene and the subsequent reaction with phenol to proceed according to the set path.

[0015] Preferably, in step S2, the mass concentration of solid phosgene in the solvent solution is 20-30%.

[0016] By adopting the above technical solution, solid phosgene is fully dissolved in toluene or xylene to form a uniform and stable reaction solution, ensuring the stability of the droplet addition process. This allows the solid phosgene to come into uniform contact with 2-amino-4,6-dimethoxypyrimidine after being added to the reaction vessel, and, in conjunction with the action of the catalyst, promotes the orderly progress of the reaction, avoiding side reactions caused by excessively high local concentrations.

[0017] Preferably, in step S3, the time for adding the solid phosgene solvent solution to the four-necked flask is 30-40 minutes.

[0018] By adopting the above technical solution, solid phosgene solvent is added dropwise to a four-necked flask, allowing solid phosgene to gradually enter the reaction system and slowly come into contact with the mixture formed by 2-amino-4,6-dimethoxypyrimidine, catalyst, and solvent. This avoids the violent exothermic reaction caused by a sudden increase in local concentration in the reaction system, ensuring a stable and controllable reaction process.

[0019] Preferably, in step S4, after the addition is complete, the temperature is raised to 60-90°C and the reaction is maintained for 2-4 hours. After the phenol is added, the temperature is raised to 90-110°C and the reaction is maintained for 3-6 hours.

[0020] By adopting the above technical solution, after the droplet is added, the temperature is raised and the reaction is kept at a certain temperature, which provides conditions for the reaction of 2-amino-4,6-dimethoxypyrimidine with solid phosgene, and promotes the generation and transformation of intermediates. After adding phenol, the temperature is increased and maintained for further reaction to match the reactivity requirements of the intermediate and phenol, ensuring the formation of the target product. The two-stage heating and holding process reduces the occurrence of side reactions.

[0021] Preferably, in step S5, water is added to wash until neutral, and the washing is performed 3 times. After washing, the washing solution is neutral, and the organic phase is dried with anhydrous sodium sulfate for 2-3 hours.

[0022] By adopting the above technical solution, washing with water and making the washing solution neutral can remove residual catalyst, unreacted water-soluble impurities, and salts generated in the reaction solution, avoiding the impact of impurity residues on the purity of subsequent products. The organic phase is compatible with the properties of toluene or xylene, and the liquid-liquid separation operation can achieve effective separation of the organic phase and the aqueous phase. Anhydrous sodium sulfate can adsorb residual water in the organic phase, and the drying time can ensure that the organic phase is fully dehydrated, avoiding the interference of water on subsequent vacuum distillation to recover the solvent and recrystallization purification, improving product content and yield, and ensuring solvent recovery efficiency.

[0023] Preferably, in step S6, the solvent used for recrystallization purification is a mixture of organic solvent and water, wherein the organic solvent includes one or more of ethanol, methanol or isopropanol, the volume ratio of organic solvent to water in the mixture is 1:(1-3), and the crystallization temperature is 0-5℃.

[0024] By adopting the above technical solution, ethanol, methanol, and isopropanol can all be miscible with water to form a mixed solvent. This mixed solvent has good solubility for 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine, but poor solubility for residual raw materials and by-products in the crude product, which is beneficial for the separation of the target product from impurities. Furthermore, the organic solvents used have low toxicity and are easily volatile, and can be recovered through conventional separation methods without increasing the cost of raw materials or the environmental burden.

[0025] This application provides a process for preparing 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. It has the following beneficial effects: 1. This application uses solid phosgene instead of the highly toxic phenyl chloroformate or gaseous phosgene in the prior art as raw material, and uses inexpensive toluene and xylene as solvents that are easy to react with moisture. At the same time, it selects triethylamine or pyridine as catalysts with controllable cost. Compared with the process of the prior art that relies on highly toxic raw materials or expensive catalysts, it reduces the cost of raw materials and safety risks, and meets the economic needs of industrial production.

[0026] 2. This application controls the concentration of solid phosgene solution, the dropping time, the staged heating and holding reaction parameters, and the molar ratio of catalyst to raw materials, so that the reaction proceeds in an orderly manner under mild conditions, avoiding the problems of violent reaction and many side reactions in the prior art. Combined with the subsequent three water washing to remove impurities and the specific mixed solvent recrystallization process, the product content and yield are greatly improved.

[0027] 3. The toluene and xylene selected in this application can be efficiently recovered and reused through vacuum distillation. The organic solvents such as ethanol and methanol used for recrystallization can also be recovered by conventional means. Compared with the existing technology where solvents are difficult to recover or have low recovery efficiency, this reduces solvent consumption, further reduces production costs, and improves the resource utilization rate of the process.

[0028] 4. The raw materials and solvents used in this application have low toxicity, and no large amount of harmful by-products are generated during the reaction process. The post-treatment water washing step can effectively remove water-soluble impurities and salts, reducing the content of harmful components in waste liquid and waste residue. Compared with the existing technology, which has a large amount of waste discharge and high treatment pressure, this reduces the burden of waste treatment, conforms to the development concept of green chemical industry, and is environmentally friendly. Attached Figure Description

[0029] Figure 1 This is a process flow diagram for this application. Detailed Implementation

[0030] The present application will be further described in detail below with reference to embodiments and comparative examples.

[0031] The following are the main raw materials and reagents used in the preparation examples, embodiments, and comparative examples, and their sources and specifications are as follows; unless otherwise specified, all reagents are commercially available analytical grade or higher products: 1. 2-Amino-4,6-dimethoxypyrimidine, purchased from Shanghai Yuanye Biotechnology Co., Ltd., product number: S46462.

[0032] 2. Solid phosgene (triphosgene), purchased from Hubei Xinjiecheng Chemical Technology Co., Ltd., CAS: 32315-10-9.

[0033] 3. Phenol, purchased from Shandong Chongcheng Energy Technology Co., Ltd., CAS: 108-95-2.

[0034] 4. Xylene, purchased from Shandong Zhengxing New Materials Co., Ltd., CAS: 1330-20-7.

[0035] 5. Triethylamine, purchased from Shandong Mingyu Supply Chain Management Co., Ltd., CAS: 121-44-8.

[0036] 6. Pyridine, purchased from Fuchen (Tianjin) Chemical Reagent Co., Ltd., CAS: 110-86-1.

[0037] 7. Isopropanol, purchased from Nanjing Chemical Reagent Co., Ltd., CAS: 67-63-0.

[0038] 8. Toluene, Nanjing Chemical Reagent Co., Ltd., CAS: 108-88-3.

[0039] Preparation Example 1 S1. Prepare 2-amino-4,6-dimethoxypyrimidine, solid phosgene, phenol, solvent and catalyst; The molar ratio of 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol is 1:1.25:1.1. The solvent is toluene, the catalyst is triethylamine, the amount of catalyst used is 0.075 times the molar amount of 2-amino-4,6-dimethoxypyrimidine, and the total amount of solvent used is 7.5 times the mass of 2-amino-4,6-dimethoxypyrimidine. Weigh 16.9 g (0.1 mol) of 2-amino-4,6-dimethoxypyrimidine, and calculate the molar ratio to add 10.1 g (0.125 mol) of solid phosgene and 10.3 g (0.11 mol) of phenol. The total amount of solvent toluene is 126.75 g (16.9 g × 7.5), and the amount of catalyst triethylamine is 0.765 g (0.1 mol × 0.075 × 10¹ g / mol).

[0040] S2. Dissolve solid phosgene in a portion of toluene to prepare a toluene solution of solid phosgene. The mass concentration of solid phosgene is 25%.

[0041] S3. Add 2-amino-4,6-dimethoxypyrimidine and the remaining toluene to a four-necked flask, stir to dissolve, add triethylamine, and then add a toluene solution of solid phosgene dropwise. The dripping time is 35 minutes.

[0042] S4. After the addition is complete, the temperature is raised and the reaction is maintained at this temperature. Then phenol is added, the temperature is raised again, and the reaction is maintained at this temperature again to obtain the reaction solution. After the addition was complete, the temperature was raised to 75°C and the reaction was maintained for 3 hours. After the addition of phenol, the temperature was raised to 100°C and the reaction was maintained for 4.5 hours.

[0043] S5. The reaction solution is then cooled to room temperature, washed with water until neutral, and separated to obtain the organic phase. The organic phase is then dried and filtered. The washing process involved adding water three times, and the washing solution was neutral after washing. The organic phase was then dried with anhydrous sodium sulfate for 2.5 hours.

[0044] S6. The filtered organic phase was subjected to vacuum distillation to recover toluene, and a crude product was obtained. The crude product was purified by recrystallization to obtain pure 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. The solvent used for recrystallization is a mixture of ethanol and water, with a volume ratio of ethanol to water of 1:2, and the crystallization temperature is 2.5℃. After recovering toluene by vacuum distillation, the crude product was added to an ethanol-water (1:2) mixed solvent, heated to dissolve, cooled to 2.5℃ to crystallize, filtered and dried to obtain the pure product.

[0045] Preparation Example 2 S1. Prepare 2-amino-4,6-dimethoxypyrimidine, solid phosgene, phenol, solvent and catalyst; The molar ratio of 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol is 1:1.0:1.0. The solvent is xylene, the catalyst is pyridine, the amount of catalyst is 0.05 times the molar amount of 2-amino-4,6-dimethoxypyrimidine, and the total amount of solvent is 5 times the mass of 2-amino-4,6-dimethoxypyrimidine. Weigh 16.9 g (0.1 mol) of 2-amino-4,6-dimethoxypyrimidine, and calculate 6.4 g (0.1 mol) of solid phosgene and 9.4 g (0.1 mol) of phenol by molar ratio. The total amount of xylene solvent is 84.5 g (16.9 g × 5), and the amount of pyridine catalyst is 0.395 g (0.1 mol × 0.05 × 79 g / mol).

[0046] S2. Dissolve solid phosgene in a portion of xylene to prepare a xylene solution containing solid phosgene. The mass concentration of solid phosgene is 20%.

[0047] S3. Add 2-amino-4,6-dimethoxypyrimidine and the remaining xylene to a four-necked flask, stir to dissolve, add pyridine, and then add a xylene solution of solid phosgene dropwise. The dripping time is 30 minutes.

[0048] S4. After the addition is complete, the temperature is raised and the reaction is maintained at this temperature. Then phenol is added, the temperature is raised again, and the reaction is maintained at this temperature again to obtain the reaction solution. After the addition was complete, the temperature was raised to 60°C and the reaction was maintained for 2 hours. After the addition of phenol, the temperature was raised to 90°C and the reaction was maintained for 3 hours.

[0049] S5. The reaction solution is then cooled to room temperature, washed with water until neutral, and separated to obtain the organic phase. The organic phase is then dried and filtered. The washing process involved three water additions, resulting in a neutral washing solution. The organic phase was then dried with anhydrous sodium sulfate for two hours.

[0050] S6. The filtered organic phase was subjected to vacuum distillation to recover xylene, and the crude product was purified by recrystallization to obtain pure 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. The solvent used for recrystallization is a mixture of methanol and water, with a volume ratio of methanol to water of 1:1, and the crystallization temperature is 0℃. After recovering xylene by vacuum distillation, the crude product was added to a methanol-water (1:1) mixed solvent, heated to dissolve, cooled to 0°C to crystallize, filtered and dried to obtain the pure product.

[0051] Preparation Example 3 S1. Prepare 2-amino-4,6-dimethoxypyrimidine, solid phosgene, phenol, solvent and catalyst; The molar ratio of 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol is 1:1.5:1.2; the solvent is a mixture of toluene and xylene in a volume ratio of 1:1; the catalyst is a mixture of triethylamine and pyridine in a molar ratio of 1:1; the amount of catalyst used is 0.1 times the molar amount of 2-amino-4,6-dimethoxypyrimidine; and the total amount of solvent used is 10 times the mass of 2-amino-4,6-dimethoxypyrimidine. 16.9 g (0 0.1 mol) 2-amino-4,6-dimethoxypyrimidine, calculated by molar ratio, 14.4 g (0.15 mol) solid phosgene, 11.3 g (0.12 mol) phenol, solvent toluene and xylene mixture (1:1) total amount of 169 g (16.9 g × 10), catalyst triethylamine and pyridine mixture (1:1) total amount of 0.9 g (0.1 mol × 0.1 × (101 + 79) / 2 g / mol).

[0052] S2. Dissolve solid phosgene in a portion of the mixed solvent to prepare a mixed solvent solution of solid phosgene; The mass concentration of solid phosgene is 30%.

[0053] S3. Add 2-amino-4,6-dimethoxypyrimidine and the remaining mixed solvent to a four-necked flask, stir to dissolve, add the catalyst mixture, and then add the mixed solvent solution of solid phosgene dropwise. The dripping time is 40 minutes.

[0054] S4. After the addition is complete, the temperature is raised and the reaction is maintained at this temperature. Then phenol is added, the temperature is raised again, and the reaction is maintained at this temperature again to obtain the reaction solution. After the addition was complete, the temperature was raised to 90°C and the reaction was maintained for 4 hours. After the addition of phenol, the temperature was raised to 110°C and the reaction was maintained for 6 hours.

[0055] S5. The reaction solution is then cooled to room temperature, washed with water until neutral, and separated to obtain the organic phase. The organic phase is then dried and filtered. The washing process involved three water additions, followed by a neutral washing solution. The organic phase was then dried with anhydrous sodium sulfate for three hours.

[0056] S6. The filtered organic phase is subjected to vacuum distillation to recover the mixed solvent and obtain a crude product. The crude product is purified by recrystallization to obtain pure 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine. The solvent used for recrystallization is a mixture of isopropanol and water, with a volume ratio of isopropanol to water of 1:3, and the crystallization temperature is 5℃. After recovering the mixed solvent by vacuum distillation, the crude product was added to a mixture of isopropanol and water (1:3), heated to dissolve, cooled to 5°C to crystallize, filtered and dried to obtain the pure product.

[0057] Comparative Example 1 The only difference from Example 1 is that solid phosgene is replaced with an equimolar amount of phenyl chloroformate, and no solvent solution of solid phosgene is prepared; instead, pure phenyl chloroformate is added dropwise.

[0058] Comparative Example 2 The only difference from Example 1 is that the solvent toluene is replaced with dichloromethane, while the total amount of solvent used is still 7.5 times the mass of 2-amino-4,6-dimethoxypyrimidine.

[0059] Comparative Example 3 The only difference from Example 1 is that the catalyst triethylamine is replaced with sodium hydroxide, and the amount used is still 0.075 times the molar amount of 2-amino-4,6-dimethoxypyrimidine.

[0060] Comparative Example 4 The only difference from Example 1 is that the molar ratio of 2-amino-4,6-dimethoxypyrimidine: solid phosgene: phenol is adjusted to 1:0.8:1.1.

[0061] Comparative Example 5 The only difference from Example 1 is that, after the addition is completed in step S4, the temperature is raised to 50°C.

[0062] Comparative Example 6 The only difference from Example 1 is that pure ethanol is used as the solvent for recrystallization in step S6.

[0063] Comparative Example 7 The only difference from Example 1 is that the toluene solution of solid phosgene is added dropwise over 10 minutes in step S3.

[0064] Comparative Example 8 The only difference from Example 1 is that the total amount of solvent used is 4 times the mass of 2-amino-4,6-dimethoxypyrimidine.

[0065] I. Product Yield and Purity (Content) Testing Experimental content The dried pure products of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine from Preparation Examples 1-3 and Comparative Examples 1-8 were selected as test samples. Three samples of each type were prepared in parallel, and the sample weight of each sample was 2.0 g.

[0066] The experimental equipment used was an electronic analytical balance, model FA2004N, with an accuracy of ±0.001g, and a high-performance liquid chromatograph, model Agilent 1260, equipped with a C18 column of 4.6mm×250mm and 5μm. The detection standards were in accordance with "Determination of Purity of Pyrimidine Intermediates by High Performance Liquid Chromatography" (HG / T4850-2020) and "Quality Control Specifications for Chemical Synthetic Drug Intermediates".

[0067] Purity detection procedure: Prepare a methanol-water (volume ratio 7:3) mobile phase, set the flow rate to 1.0 mL / min, the detection wavelength to 254 nm, the column temperature to 30 ℃, and the injection volume to 20 μL; prepare a standard solution (4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine standard, purity ≥99.8%) and a sample solution with a concentration of 1.0 mg / mL, respectively, sonicate for 10 minutes, allow to stand and filter, inject and analyze in sequence, and record the chromatographic peak area of ​​each solution.

[0068] Yield calculation steps: Accurately weigh the total mass of the final dried pure product from each preparation example / comparative example (denoted as ). The theoretical yield (denoted as ) is calculated based on reaction stoichiometry. Theoretical yield = 2-amino-4,6-dimethoxypyrimidine feed molar amount × target product molar mass (274.27 g / mol), yield calculation formula is: yield (%) = ( / ()×100%, and take the average value of 3 parallel samples as the final result.

[0069] II. Solvent Recovery Rate Detection Experimental content The reaction solvents of Preparation Examples 1-3 and Comparative Examples 1-8 were selected as test objects, and solvent recovery tests were carried out in parallel three times for each type of process.

[0070] The experimental equipment used was a vacuum distillation apparatus, including a vacuum gauge and thermometer with a vacuum accuracy of ±0.001MPa and a temperature accuracy of ±1℃, an electronic analytical balance, and a gas chromatograph, model Agilent 7890A, equipped with an HP-5 column. The detection standard referred to "Methods for Recovery and Purity Determination of Organic Solvents" (GB / T32122-2015).

[0071] Recovery steps: Accurately weigh the total mass of solvents used in each process (denoted as...). Solvent recovery was performed under the vacuum distillation conditions (vacuum degree 0.08-0.09 MPa, distillation temperature 60-80℃) set in the preparation process. The recovered solvent was collected and cooled to room temperature, and the mass of the recovered solvent was weighed (denoted as ). The purity of the recovered solvent was determined by gas chromatography. The chromatographic conditions were set as follows: column temperature 80℃ held for 5 min, heating rate 10℃ / min to 150℃, detector FID, and carrier gas. The flow rate was 1.0 mL / min, and the purity value of the recovered solvent was recorded.

[0072] The formula for calculating solvent recovery rate is: Recovery rate (%) = ( / ()×100%, and take the average of 3 parallel experiments as the final result.

[0073] III. Waste Discharge and Environmental Compatibility Testing Experimental content The preparation processes of Preparation Examples 1-3 and Comparative Examples 1-8 were selected as test subjects, and all waste liquids, waste residues and waste gases generated during the reaction process were collected.

[0074] The experimental equipment used included a COD digester (model DRB200), a UV-Vis spectrophotometer (model UV759), a gas chromatograph-mass spectrometer (GC-MS, model Agilent 7890A-5975C), and an electronic analytical balance. The testing standards referred to were "Determination of Chemical Oxygen Demand (COD) in Water - Dichromate Method" (GB11914-89), "Leaching Toxicity of Solid Waste - Sulfuric Acid and Nitric Acid Method" (HJ / T299-2007), and "Integrated Emission Standard of Air Pollutants" (GB16297-1996).

[0075] Waste liquid testing procedure: Collect all waste liquid after washing and separation, measure the waste liquid volume (V, accurate to 0.01L), digest according to GB11914-89 standard, and determine the COD value (mg / L) using a UV-Vis spectrophotometer. Calculate the total COD emission (g) = COD value × V × .

[0076] Waste residue testing steps: Collect all solid waste residues, including the filtered desiccant, recrystallization mother liquor evaporation residue, etc., and accurately weigh the mass (recorded as ). The leachate was prepared according to the HJ / T299-2007 standard (accurate to 0.01g), and the content of toxic and harmful substances such as chlorides and heavy metals in the leachate was tested.

[0077] Exhaust gas detection steps: Install a gas absorption device at the tail gas outlet of the reaction unit to absorb the solvents and toxic gases volatilized during the reaction. Use GC-MS to determine the content of toxic components in the absorption liquid, such as phenyl chloroformate and dichloromethane. Calculate the exhaust gas emission per unit product (mg / kg) = (total mass of toxic components ÷ pure product mass) × .

[0078] Table 1 Product Yield and Purity (Content) Test Data

[0079] Table 2 Solvent recovery rate test data

[0080] Table 3. Waste Discharge and Environmental Compatibility Testing

[0081] 1. As can be seen from Examples 1-3 and Comparative Example 1 and Table 1, solid phosgene is the core raw material of this process. As a low-toxicity and stable phosgene substitute, it can efficiently generate the target intermediate in the reaction, ensuring product yield and purity. If it is replaced with the traditional raw material phenyl chloroformate, there are not only safety hazards of high toxicity and volatility, but also the product yield drops to 80.5% and the purity is only 97.2%, and the emission of toxic components in the waste gas surges, destroying the synergistic effect of high safety and high product quality.

[0082] 2. Based on Examples 1-3 and Comparative Example 2, and in conjunction with Tables 2 and 3, it can be seen that toluene and xylene have low toxicity and are easily separated from water, with solvent recovery rates exceeding 90%. However, if replaced with more toxic dichloromethane, the solvent recovery rate drops to only 65.3%, the COD emission of the waste liquid increases to 97.6 g / batch, and the emission of toxic components in the waste gas reaches 203.7 mg / kg. This not only hinders solvent recycling but also exacerbates the environmental burden and undermines the green and environmentally friendly advantages of the process.

[0083] 3. Based on Examples 1-3 and Comparative Example 3, and in conjunction with Tables 1 and 3, it can be seen that triethylamine and pyridine can promote the reaction in a mild and efficient manner, ensuring product yield and purity. If replaced with inorganic alkali sodium hydroxide, the catalyst has poor compatibility with the reaction system, resulting in a product yield of only 74.3%, a purity of 96.5%, and a waste residue generation of 15.7g / batch, leading to an increase in side reactions and a significant increase in the pressure of waste treatment.

[0084] 4. Based on Examples 1-3 and Comparative Example 4 and Table 1, it can be seen that solid phosgene can fully activate amino groups to generate intermediates. If the molar ratio is too low (1:0.8), the raw material reaction is incomplete, the product yield drops to 72.8%, the purity is only 95.8%, and the amount of residual raw material in the crude product increases, which destroys the synergistic effect of raw material utilization and product quality.

[0085] 5. Based on Examples 1-3 and Comparative Example 5 and Table 1, it can be seen that the temperature range of 60-90℃ after the addition can promote the full reaction and avoid side reactions. If the temperature is too low (50℃), the intermediate is not fully formed, and the conversion rate of the subsequent reaction with phenol decreases. The product yield is only 74.9% and the purity is 96.1%, which cannot achieve the synergistic improvement of reaction efficiency and product purity.

[0086] 6. Based on Examples 1-3 and Comparative Example 6, and in conjunction with Tables 1 and 2, it can be seen that the mixed solvents of ethanol, methanol, or isopropanol and water can precisely control the crystallization purity of the product. If pure ethanol is used instead, impurities are difficult to separate effectively, and the product purity is only 98.2%, which cannot achieve efficient purification of crude product and undermines the technical effect of high product purity.

[0087] 7. Based on Examples 1-3 and Comparative Example 7, and in conjunction with Tables 1 and 3, it can be seen that slow addition over 30-40 minutes is the core operation for controlling the reaction process. This can avoid violent exothermic reactions and side reactions caused by excessively high local concentrations. If the addition time is too short, the reaction will run out of control and generate a large number of by-products. The product yield will be only 69.8%, the purity will be 94.7%, and the COD emission of the waste liquid will increase to 112.6g / batch.

[0088] 8. Based on Examples 1-3 and Comparative Example 8, and in conjunction with Tables 1 and 2, it can be seen that a solvent dosage of 5-10 times the mass of 2-amino-4,6-dimethoxypyrimidine is crucial to ensure complete dissolution of the raw materials and to ensure uniform reaction. If the dosage is too low, the raw materials will not dissolve completely, the reaction system will be in a suspended state, the mass transfer efficiency will decrease, the product yield will drop to 65.6%, the purity will drop to 93.9%, and the solvent recovery rate will also drop to 88.5%, thus destroying the synergistic effect of reaction sufficiency and solvent recovery efficiency.

[0089] Although embodiments of this application have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of this application, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for preparing 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine, characterized in that, Includes the following steps: S1. Prepare 2-amino-4,6-dimethoxypyrimidine, solid phosgene, phenol, solvent and catalyst; S2. Dissolve solid phosgene in a portion of the solvent to prepare a solvent solution of solid phosgene; S3. Add 2-amino-4,6-dimethoxypyrimidine and the remaining solvent to a four-necked flask, stir to dissolve, add the catalyst, and then add the solvent solution of the solid phosgene dropwise. S4. After the addition is complete, the temperature is raised and the reaction is maintained at this temperature. Then phenol is added, the temperature is raised again, and the reaction is maintained at this temperature again to obtain the reaction solution. S5. The reaction solution is then cooled to room temperature, washed with water until neutral, and separated to obtain the organic phase. The organic phase is then dried and filtered. S6. The filtered organic phase is subjected to vacuum distillation to recover the solvent, and a crude product is obtained. The crude product is purified by recrystallization to obtain pure 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine.

2. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S1, the molar ratio of 2-amino-4,6-dimethoxypyrimidine, solid phosgene, and phenol is 1:(1.0-1.5):(1.0-1.2).

3. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S1, the solvent is one or more of toluene and xylene.

4. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, The catalyst is one or more of triethylamine and pyridine.

5. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, The amount of catalyst used is 0.05-0.1 times the molar amount of 2-amino-4,6-dimethoxypyrimidine.

6. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S2, the mass concentration of solid phosgene in the solvent solution is 20-30%.

7. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S3, the time for adding the solid phosgene solvent solution to the four-necked flask is 30-40 minutes.

8. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S4, after the addition is complete, the temperature is raised to 60-90°C and the reaction is maintained for 2-4 hours. After adding phenol, the temperature is raised to 90-110°C and the reaction is maintained for 3-6 hours.

9. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S5, water is added and washed until neutral. The washing is repeated 3 times. After washing, the washing solution is neutral. The organic phase is dried with anhydrous sodium sulfate for 2-3 hours.

10. The preparation process of 4,6-dimethoxy-2-((phenoxycarbonyl)amino)-pyrimidine according to claim 1, characterized in that, In step S6, the solvent used for recrystallization purification is a mixture of organic solvent and water. The organic solvent includes one or more of ethanol, methanol, or isopropanol. The volume ratio of the organic solvent to water in the mixture is 1:(1-3), and the crystallization temperature is 0-5℃.

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